1. Field of the Invention
The invention relates to novel porphycene compounds and pharmaceutical compositions containing these compounds which are useful for therapeutic treatment.
2. Discussion of the Background
During the past few years there has developed a widespread recognition that modern, though sophisticated, cancer diagnosis and treatments have served neither to reduce overall the number of case of reported cancers in the U.S.A. nor, save the notable cases, the death rate. This is a disheartening result for the billions of dollars invested in conquering the disease. Moreover, surgery, radiotherapy and chemotherapy are all associated with major debilitating side effects such as trauma, severe immunosuppression or toxicity which are not easily surmounted by patients already compromised by ill-health.
Early work in the 1970's followed by rapidly expanding studies in the 1980's, has shown that photodynamic therapy (PDT) offers a viable, less toxic and generally less painful avenue to treatment of cancer. Not all cancers are candidates for PDT. However, intractable tumor masses (solid tumors, frequently characterized by poorly developed vascular system), sometimes inoperable, and with no good track record for treatment by established therapeutic procedures, appear to be targets for PDT.
Dougherty et al (Cancer Res., 1978, 38, 2628) pioneered the field with infusion of photoactivatable dyes, followed by appropriate long wavelength radiation of the tumors (600+ nm) to generate a lethal short-lived species of oxygen which destroyed the neoplastic cells. Early experiments utilized a mixture termed haematoporphyrin derivative (HPD). The deficiencies of HPD, especially prolonged phototoxicity caused by retained HPD components in human skin led to its displacement by a purified fraction termed dihaematoporphyrin ether (DHE) which, although yielding improvements over HPD, nevertheless still suffered certain practical limitations. Relatively weak absorption in the wavelength range 600-700 nm, retention in dermal cells (potentially leading to phototoxicity) and uncertain chemical constitution are all known negative features. The great majority of the earlier PDT agents studied have been derived from natural sources (porphyrins, chlorins, purpurins, etc.) or from known chemicals originating in the dyestuffs industry (e.g., cyanine dyes).
As the deficiencies of these earlier agents have become apparent, it also becomes possible to define activity parameters for improved chemically pure photoactivatable dyes for PDT therapy, available by chemical synthesis. Moreover, the products of synthesis lend themselves more readily to further chemical structural manipulation than do the naturally-occurring starting materials which can be expensive and bear chemically sensitive constituents. The synthesis of the novel porphycene macrocycle embracing four pyrrole rings, has been described by Vogel and coworkers. Alkylated porphycenes have also been prepared (R=Me, Et, n-Pr, n-octyl, phenyl) and the photochemical properties determined. The suitability of these compounds for PDT was noted and confirmed in animal studies (Cancer Letters, 1989, 44, 1).
Pyrrole-containing ring systems larger than porphycene have also been prepared and evaluated as photosensitizers. Sessler et al have prepared and studied texaphyrin (J. Am. Chem. Soc., 1988, 110, 5586) and Woodward et al and Johnson et al have prepared and investigated sapphyrin ring systems. Additionally, the platyrin system has been studied by LeGoff (Tetrahedron, Lett., 1978, 4225; J. Org. Chem., 1987, 710) and vinylogous porphyrins have been studied by Franck (Angew. Chem., 1986, 98, 1107; Angew. Chem. Int. Ed. Eng., 1986, 25, 1100; Angew. Chem., 1988, 100, 1203; Angew. Chem. Int. Ed. Eng., 1988, 27, 1170).
A need continues to exist, therefore, for new compounds for use in PDT therapy, which compounds are easily available, have low intrinsic toxicity, are efficient photosensitizers for singlet oxygen production, have selective uptake in rapidly proliferating cells, are rapidly or at least moderately rapidly degraded and eliminated from the tissues after administration and which are available as chemically pure and stable compounds easily subject to synthetic modification.